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-Linolenic Acid, Coronary Heart Disease, and Prostate Cancer
Laboratoire Nutrition Vieillissement et Maladies Cardiovasculaires (NVMCV) UFR de Médecine Université Joseph Fourier Grenoble, France
Dear Editor:
Using sophisticated meta-analyses, Brouwer et al. report that a high 
-linolenic acid (ALA)1 intake is associated with a reduced risk of fatal coronary heart disease (CHD) but an increased risk of prostate cancer (PC) (1). They conclude that (n-3) fatty acids from fish (and not ALA) should be recommended for the prevention of CHD (1). Medical advice based on observational studies (with their many confounders), and not on trial data, is surprising. Although Brouwer et al. do not cite all of the trials with ALA, it would have been fair to carefully describe the Lyon Diet Heart Study (2,3), in which 605 patients were actually randomized (and not 192 and 219 in each group), and report that, using a multivariate model, ALA proved to be the unique dietary factor associated with risk reduction (3). Finally, Brouwer et al. should have mentioned that fewer patients who consumed the ALA-rich diet developed cancer (4). Because of the small number of cases, it is not possible to draw any conclusions about PC itself. However, because the Lyon trial is the only randomized dietary trial with ALA and cancer data, it would have been fair to mention the point.
Brouwer et al. use the framework of a systematic review, a prerequisite for a credible meta-analysis (5). The major drawback is heterogeneity; if studies are too disparate, it is illogical to try to group them together. Paradoxically, Brouwer et al. discuss the heterogeneity of the studies included in their meta-analysis, but remain confident in their results. In addition, they omit some studies that show no association between ALA and PC, although these are cited by other authors (6). They use studies with either dietary ALA or ALA concentrations in various samples (as if there was a normalization of these disparate measurements), and they combine prospective studies, case-control studies, and nested case-control studies. Finally, they ignore heterogeneity between populations in terms of lifestyle and dietary sources of ALA, although those were very different in Europe, the U.S., and Uruguay, especially between 1982 and 2003. They claim that individuals categorized as high consumers (vs. low consumers) in the different studies can be consistently pooled and compared to calculate overall risk ratios, which is not credible.
The food sources of ALA in the various studies are indeed another major concern; adjustments were performed in only a minority of these studies, whereas data from all are combined. Finally, biological rationality is crucially important when evaluating observational studies. Two reports may help in understanding this complex issue. In a large cohort study, ALA intake as evaluated in 1984 in 47,866 men did not correspond to the risk of PC (2965 cases) (7). This could have closed the debate once and for all. However, among these subjects, 448 cases were categorized as "advanced PC" and associated with increased intakes of ALA from both animal and nonanimal sources (7), suggesting that ALA may stimulate invasiveness rather than initiation of PC. This is only consistently studied in one report that measured prostatic tissue levels of ALA in relation to the histopathological characteristics associated with invasiveness in men undergoing prostatectomy (8). In contradiction to epidemiological data (7), prostatic ALA (including invasive tumors) was significantly lower in study subjects than in controls (8).
Thus, the evidence that ALA may favor any form of PC is very weak, and Brouwer et al. do not clarify the point. Instead of making recommendations that could mislead many people who would lose the benefits of increasing their consumption of ALA, they should only conclude that the issue deserves more research.
FOOTNOTES
1 Abbreviations used: ALA, -linolenic acid; CHD, coronary heart disease; PC, prostate cancer. 
Manuscript received 2 July 2004. Revision accepted 15 September 2004.
LITERATURE CITED
1. Brouwer, I. A., Katan, M. B. & Zock, P. L. (2004) Dietary-linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J. Nutr. 134:919-922.
2. de Lorgeril, M., Renaud, S., Mamelle, N., Salen, P., Martin, J. L., Monjaud, I., Guidollet, J., Touboul, P. & Delaye, J. (1994) Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343:1454-1459.[Medline]
3. de Lorgeril, M., Salen, P., Martin, J. L., Monjaud, I., Delaye, J. & Mamelle, N. (1999) Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation 99:779-785.
4. de Lorgeril, M., Salen, P., Martin, J. L., Monjaud, I., Boucher, P. & Mamelle, N. (1998) Mediterranean dietary pattern in a randomized trial. Prolonged survival and possible reduced cancer rate. Arch. Intern. Med. 158:1181-1187.
5. Koretz, R. L. (2002) Methods of meta-analysis: an analysis. Curr. Opin. Clin. Nutr. Metab. Care 5:467-474.[Medline]
6. Sinclair, A. J., Attar-bashi, N. & Li, D. (2002) What is the role of alapha-linolenic acid for mammals. Lipids 37:1113-1123.[Medline]
7. Leitzmann, M. F., Stampfer, M. J., Michaud, D. S., Augustsson, K., Colditz, G. C., Willett, W. C. & Giovannucci, E. L. (2004) Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am. J. Clin. Nutr. 80:204-216.
8. Freeman, V. L., Meydani, M., Yong, S., Pyle, J., Flanigan, R. C., Waters, W. B. & Wojcik, E. M. (2000) Prostatic levels of fatty acids and the histopathology of localized prostate cancer. J. Urol. 164:2168-2172.[Medline]
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